The rs1883832 Polymorphism (CD40-1C>T) Affects the Intensity of IgA Responses after BNT162b2 Vaccination

The effectiveness of coronavirus disease 2019 (COVID-19) vaccination strategies is affected by several factors, including the genetic background of the host. In our study, we evaluated the contribution of the functional polymorphism rs1883832 affecting the Kozak sequence of the TNFSF5 gene (c.-1C>T), encoding CD40, to humoral immune responses after vaccination with the spike protein of SARS-CoV-2. The rs1883832 polymorphism was analyzed by PCR-RFLP in 476 individuals (male/female: 216/260, median age: 55.0 years, range: 20−105) of whom 342 received the BNT162b2 mRNA vaccine and 134 received the adenovirus-based vector vaccines (67 on ChAdOx1-nCoV-19 vaccine, 67 on Ad.26.COV2.S vaccine). The IgG and IgA responses were evaluated with chemiluminescent microparticle and ELISA assays on days 21, 42, and 90 after the first dose. The T allele of the rs1883832 polymorphism (allele frequency: 32.8%) was significantly associated with lower IgA levels and represented, as revealed by multivariable analysis, an independent risk factor for reduced anti-spike protein IgA levels on days 42 and 90 following BNT162b2 mRNA vaccination. Similar to serum anti-spike IgA levels, a trend of lower anti-spike IgA concentrations in saliva was found in individuals with the T allele of rs1883832. Finally, the intensity of IgA and IgG responses on day 42 significantly affected the prevalence of COVID-19 after vaccination. The rs1883832 polymorphism may be used as a molecular predictor of the intensity of anti-spike IgA responses after BNT162b2 mRNA vaccination.

Dynamics of Anti-SARS-CoV-2 IgA and IgG Responses and Their Protective Effect against Fatal Disease after Booster COVID-19 Vaccination.

During the post-coronavirus disease (COVID-19) era, a primary question is whether booster vaccination is effective against severe COVID-19 and should be recommended, particularly to individuals at high risk for severe disease (i.e., the elderly or those with additional severe comorbidities). From December 2020 to February 2023, a cohort study was conducted to estimate IgG and IgA immunogenicity and the dynamics of booster mono- and bivalent COVID-19 mRNA vaccines in 260 individuals (male/female: 114/146, median age: 68 years, interquartile range (IQR) = 31) who initially received either mRNA (218) or adenovirus-vector-based vaccines (42). Participants were followed until the 90th day after the third booster dose. Our cohort study indicated a beneficial effect of booster vaccination on the magnitude of IgG and IgA severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibodies. We found that second and third booster doses were more protective than one against fatal disease (p = 0.031, OR 0.08). In conclusion, booster COVID-19 vaccination should be strongly recommended, especially to individuals at high risk for severe/fatal disease.

Broad-Spectrum and Gram-Negative-Targeting Antibiotics Differentially Regulate Antibody Isotype Responses to Injected Vaccines.

Antibiotics are extensively used worldwide for the treatment of common infections by agents such as E. coli and Salmonella. They also represent the most common cause of alteration of the microbiota in people. We addressed whether broad-spectrum and Gram-negative-targeting antibiotics differentially regulate systemic and mucosal immune responses to vaccines. Antibiotics treatment enhances serum IgG1 responses in mice immunized systemically with a model polyvalent vaccine. This increase was not seen for other IgG subclasses and was dependent on the immunogenicity of vaccine antigens. The broad-spectrum antibiotic cocktail also enhanced serum IgA responses. Interestingly, both the broad spectrum and the antibiotic targeting Gram-negative bacteria enhanced the number of IgA antibody secreting cells in the intestinal lamina propria. This effect was unlikely to be due to an increase in cells expressing gut-homing receptors (i.e., CCR9 and α4ß7) in peripheral tissues. On the other hand, the microbiome in mice treated with antibiotics was characterized by an overall reduction of the number of firmicutes. Furthermore, Bacteroidetes were increased by either treatment, and Proteobacteria were increased by the broad-spectrum antibiotics cocktail. Thus, immunoglobulin isotype and subclass responses are differentially regulated by oral antibiotics treatment and the gut microbiota shapes mucosal antibody responses after systemic immunization.

A Systems Biology Approach Identifies B Cell Maturation Antigen (BCMA) as a Biomarker Reflecting Oral Vaccine Induced IgA Antibody Responses in Humans.

Vaccines against enteric diseases could improve global health. Despite this, only a few oral vaccines are currently available for human use. One way to facilitate such vaccine development could be to identify a practical and relatively low cost biomarker assay to assess oral vaccine induced primary and memory IgA immune responses in humans. Such an IgA biomarker assay could complement antigen-specific immune response measurements, enabling more oral vaccine candidates to be tested, whilst also reducing the work and costs associated with early oral vaccine development. With this in mind, we take a holistic systems biology approach to compare the transcriptional signatures of peripheral blood mononuclear cells isolated from volunteers, who following two oral priming doses with the oral cholera vaccine Dukoral®, had either strong or no vaccine specific IgA responses. Using this bioinformatical method, we identify TNFRSF17, a gene encoding the B cell maturation antigen (BCMA), as a candidate biomarker of oral vaccine induced IgA immune responses. We then assess the ability of BCMA to reflect oral vaccine induced primary and memory IgA responses using an ELISA BCMA assay on a larger number of samples collected in clinical trials with Dukoral® and the oral enterotoxigenic Escherichia coli vaccine candidate ETVAX. We find significant correlations between levels of BCMA and vaccine antigen-specific IgA in antibodies in lymphocyte secretion (ALS) specimens, as well as with proportions of circulating plasmablasts detected by flow cytometry. Importantly, our results suggest that levels of BCMA detected early after primary mucosal vaccination may be a biomarker for induction of long-lived vaccine specific memory B cell responses, which are otherwise difficult to measure in clinical vaccine trials. In addition, we find that ALS-BCMA responses in individuals vaccinated with ETVAX plus the adjuvant double mutant heat-labile toxin (dmLT) are significantly higher than in subjects given ETVAX only. We therefore propose that as ALS-BCMA responses may reflect the total vaccine induced IgA responses to oral vaccination, this BCMA ELISA assay could also be used to estimate the total adjuvant effect on vaccine induced-antibody responses, independently of antigen specificity, further supporting the usefulness of the assay.

Mucosal IgA Responses: Damaged in Established HIV Infection-Yet, Effective Weapon against HIV Transmission.

HIV infection not only destroys CD4+ T cells but also inflicts serious damage to the B-cell compartment, such as lymphadenopathy, destruction of normal B-cell follicle architecture, polyclonal hypergammaglobulinemia, increased apoptosis of B cells, and irreversible loss of memory B-cell responses with advanced HIV disease. Subepithelial B cells and plasma cells are also affected, which results in loss of mucosal IgG and IgA antibodies. This leaves the mucosal barrier vulnerable to bacterial translocation. The ensuing immune activation in mucosal tissues adds fuel to the fire of local HIV replication. We postulate that compromised mucosal antibody defenses also facilitate superinfection of HIV-positive individuals with new HIV strains. This in turn sets the stage for the generation of circulating recombinant forms of HIV. What can the mucosal B-cell compartment contribute to protect a healthy, uninfected host against mucosal HIV transmission? Here, we discuss proof-of-principle studies we have performed using passive mucosal immunization, i.e., topical administration of preformed anti-HIV monoclonal antibodies (mAbs) as IgG1, dimeric IgA1 (dIgA1), and dIgA2 isotypes, alone or in combination. Our data indicate that mucosally applied anti-HIV envelope mAbs can provide potent protection against mucosal transmission of simian-human immunodeficiency virus. Our review also discusses the induction of mucosal antibody defenses by active vaccination and potential strategies to interrupt the vicious cycle of bacterial translocation, immune activation, and stimulation of HIV replication in individuals with damaged mucosal barriers.